Is CASQ2 p.Arg253Ser (c.757C>A) pathogenic?

CASQ2 p.Arg253Ser (c.757C>A) is classified Uncertain significance in CASQ2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-29). AlphaMissense: ambiguous (0.4945); Very rare (popmax 0.00694%, afr); Associated with Cardiovascular phenotype.

How common is CASQ2 p.Arg253Ser (c.757C>A) in the general population?

CASQ2 p.Arg253Ser (c.757C>A) is very rare (popmax 0.00694%, afr) (gnomAD).

What do computational predictors say about CASQ2 p.Arg253Ser (c.757C>A)?

AlphaMissense predicts ambiguous (score 0.4945) — an in-silico prediction, not a clinical call.

CASQ2 p.Arg253Ser

Q: What condition is associated with CASQ2 p.Arg253Ser (c.757C>A)?

CASQ2 p.Arg253Ser (c.757C>A) is associated with Cardiovascular phenotype, catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia 2 (ClinVar).

c.757C>A · rs727504510 · VCV178880

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4945 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00694%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.4945	ambiguous
REVEL	0.522	indeterminate
SaProt	LLR -8.33	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 67 kb · p 0.83 · regional, not allelic
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00694% African / African-American · 5/72,060 alleles

Filtering AF 0.00273% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00177%

Overall 0.000498% 8/1,605,736 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00694%	14,412
East Asian	0.00224%	44,650
European (non-Finnish)	0.00017%	589,001

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CASQ2
Protein: p.Arg253Ser
Coding: c.757C>A
MANE Select: NM_001232
dbSNP: rs727504510
Type: single nucleotide variant
Location: chr1:115725534 (GRCh38)
Gene constraint: LOEUF 1.322 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.63 · 4 PDB

Full CASQ2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: catecholaminergic polymorphic ventricular tachycardia 1 catecholaminergic polymorphic ventricular tachycardia 2

Similar variants

CASQ2 p.Arg253Cys Uncertain significance ★★ ⚠ same residue
CASQ2 p.Arg253His Uncertain significance ★★ ⚠ same residue
CASQ2 p.Arg253Leu Uncertain significance ★ ⚠ same residue
CASQ2 p.Arg253Pro Uncertain significance ★ ⚠ same residue
CASQ2 p.Arg253= Likely benign ★ same residue
CASQ2 c.235-2A>G Likely pathogenic ★★ same condition
CASQ2 c.319+2T>G Likely pathogenic ★★ same condition
CASQ2 c.320-2A>G Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/casq2-p-arg253ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown